Angiogenesis plays a critical role in tumor progression, invasion and metastasis. It has become an attractive molecular target for chemotherapy. Anti-angiogenic tumor therapies focus on several regulatory and signaling molecules that control the process of formation and sprouting of new blood vessels. In particular, inhibition of vascular endothelial growth factor (VEGF) has shown antitumor activity in clinical settings, which results in starvation or apoptosis of tumor cells. An example is Bevacizumab (Avastin) which is a monoclonal antibody that specifically recognizes and binds to VEGF-A. Avastin is currently approved by the U.S. Food and Drug Administration (FDA) as a first or second line therapeutic agent for treatment of glioblastoma and colorectal cancers (CRC), both of which are highly vascularized tumors that depend primarily on angiogenesis. Although Avastin monotherapy has been proven effective for several indications such as recurrent glioblastoma, many newly diagnosed cancer patients with glioblastoma do not respond and Avastin failed to provide a survival advantage. The mechanism of intrinsic and required resistance to Avastin is not fully elucidated, clinical investigations have suggested that other VEGF family members, including placental growth factor (PlGF), VEGF-C, VEGF-D, and cytokine angiogenic factors (CAFs), may modulate sensitivity to anti-VEGF-A (Avastin) therapy and allow regrowth of tumor-associated vasculature. This is because Avastin blocks the main flow of blood, so tumors shrink at the beginning, but the tumors may then switch dependence to other related growth factors in search of blood. Additional examples of the complex refractory nature of VEGF to Avastin were discussed in a recent review. Thus, additional angiogenesis pathways must exist that compensate for and contribute to resistance that develops to anti-VEGF-A therapy.
One of such angiogenesis pathway involves 2-(α-carboxyethyl)pyrrole (CEP) protein derivatives that are generated by radical-induced oxidation of docosahexaenoate (DHA)-containing lipids. CEP levels are elevated in ocular tissues from patients with age-related macular degeneration, as well as in human melanoma. Our studies have shown that CEPs promote angiogenesis through a previously unknown pathway. CEPs activate proangiogenic responses in a Toll-like receptor 2 (TLR-2)-dependant manner that is independent of VEGF receptors.